The antimicrobial properties of various free fatty acids and fatty acid esters such as the glycerides have been investigated for many years (Niemans C., Influence of trace amounts of fatty acids on the growth of microorganisms. Bacterial Reviews 1954; 18:147-163 and Kodicek E., The effect of unsaturated fatty acids on gram-positive bacteria. Society for Experimental Biology Symposium 1949; 3: 2180-231). These studies have confirmed that both free fatty acids (FFA) and monoglycerides (MG) are capable of inhibiting the growth of numerous types of bacteria (Kabara J. J., Lipids as host-resistant factors of human milk, Nutr. Reviews 1980; 38: 65-73, Kabara J. J., Fatty acids and derivatives as antimicrobial agents. A review. In: Kabara J. J., ed. The Pharmacological Effect of Lipids. Champaign, IL: American Oil Chemist Society, 1978: 1-14 and Knapp H. R., Melly M. A., Bactericidal effects of polyunsaturated fatty acids. J Infect Dis 1986; 154: 84-94), fungi (Wyss O., Ludwig B. J., Joiner R. R., The fungistatic and fungicidal action of fatty acids and related compounds. Arch Biochem. 1945; 7: 415-425) protozoans (Lees A. M., Korn E. D., Metabolism of unsaturated fatty acids in protozoa. Biochemistry 1966; 1475-1481) and lipid-enveloped viruses (Welsh J. K., Skurrie I. J., May J. T., Use of Semliki Forest virus to identify lipid-mediated antiviral activity and anti-alphavirus immunoglobulin A in human milk. Infect Immun 1978; 19: 395-401). Numerous studies have also described the generation of inhibitory fatty acids or derivatives by the action of lipases on triglycerides in human milk and infant formulas (Isaacs C. E., Kashyap S., Heird W. C., Thormar H., Antiviral and antibacterial lipids in human milk and infant formula feeds. Arch. Dis. Childhood 1990; 65: 861-864; Hernell O., Ward H., Blackberg L., Pereira MEA, Killing of Giardia lamblia by human milk lipases: an effect mediated by lipolysis of milk lipids. J Inf Dis 1986; 153: 715-720). Susceptibility of various bacteria to inactivation by specific fatty acids may be a factor in regulating the different species of bacteria that colonize the various niches in skin as well as the respiratory and gastrointestinal tracts.
Most investigations of the antimicrobial properties of FFA and MG have used in vitro models to evaluate the inhibitory effects of short-chain and long-chain saturated and monounsaturated fatty acids; fewer studies have been done on the inhibitory properties of long-chain polyunsaturated fatty acids. (Kabara J. J., Lipids as host-resistant factors of human milk, Nutr Reviews 1980; 38: 65-73; Kabara J. J., Fatty acids and derivatives as antimicrobial agents. A review. In: Kabara J. J., ed. The pharmacological effect of lipids. Champaign, IL: American Oil Chemist Society, 1978: 1-14 and Knapp H. R., Melly M. A., Bactericidal effects of polyunsaturated fatty acids. J Infect Dis 1986; 154: 84-94; and Thormar H., Isaacs C. E., Brown H. R., Barshatzky M. R., Pessalano T., Inactivation of enveloped viruses and killing of cells by fatty acids and monoglycerides. Antimicr Agents Chemother 1987; 31: 27-31). Results from these studies have led experts to reach the following conclusions with regard to fatty acid structure-activity relationships.
(1) In general, FFA sensitivity is considered to be a characteristic of gram-positive bacteria, with few gram-negative bacteria being sensitive. PA1 (2) Gram-negative bacteria are affected primarily by very short chain FFA (e.g., C.sub.6 or less). PA1 (3) Yeasts/fungi are affected by FFA with short chain fatty acids (e.g., C.sub.10 or less).
For many years the cause of peptic ulcer disease was widely believed to be associated with a disturbance in the balance between the presence of noxious agents found in the stomach and the operation of innate mucosal protective mechanisms. As a result, much of the research on ulcer disease during the past forty years has focused on the role of gastric acid in the genesis of peptic ulceration. While suppression of acid production with histamine 2 (H2)--receptor antagonists is effective in healing acute ulcers, the recurrence rate during the first year can be as high as 90%. This indicates that such treatment is effective in healing the ulcers but not curing the disease.
Few of the early investigations of gastric disease explored an infectious etiology until Marshall and Warren described the isolation of gram-negative spiral-shaped bacteria from biopsy specimens obtained from human subjects with gastritis and peptic ulcers (Marshall B. J., Warren J. R., Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1984; i: 1311-1315). These investigators later identified this organism as Campylobacter pyloridis. Subsequent studies have confirmed that this bacterium, currently referred to as Helicobacter pylori, is a major etiologic agent in chronic diffuse superficial (type B) gastritis and gastroduodenal ulcer disease. Evidence to support such an association is provided by studies in human volunteers that were challenged with H. pylori (Marshall B. J., Armstrong J. A., McGeechie D. B., Glancy R. J., Attempts to fulfill Koch's postulates for pyloric Campylobacter. Med. J. Aust. 1985; 142: 436-439 and Morris A., Nicholson G., Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH. Am. J. Gastroenterol 1987;82: 192-199) and the recognition of a similar association between gastric diseases and spiral organisms found in the stomachs of laboratory animals (Fox J. G., Lee A., Gastric Campylobacter-like organisms: their role in gastric disease in laboratory animals. Lab Animal Sci. 1989; 39: 543-553). While H. pylori infection is extremely common in both children and adults in many countries throughout the world, many individuals remain infected for years without developing symptoms of gastritis or ulcer disease. Reports have also appeared regarding a possible association between H. pylori infection and the development of gastric carcinoma (Parsonnett J., Friedman G. D., Vandersteen M. A., Chang Y., Vogelman J. H., Orentreich N., Sibley R. K., Helicobacter pylori infection and the dsk of gastric carcinoma, N. Engl. J. Med. 1991; 325: 1127-1131 and Nomura A., Stemmermann G. N., Chyou P. H., Kato I., Perez-Perez G., Blaser M. J., Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii, N. Engl. J. Med. 1991; 325: 1132-1136).
Histological studies have determined that H. pylori colonizes the mucus layer overlying the epithelial cells in the antral region of the stomach and does not appear to invade gastric tissue. While many antimicrobial agents exist with good activity against H. pylori in vitro, evaluation of single agents in clinical trials have not resulted in consistent long-term eradication of the organism from the upper gastrointestinal tract. Results from trials with two or more antibiotics, however, indicate that eradication of H. pylori is associated with both the resolution of gastritis and significant decreases in relapse rate of duodenal ulcers compared to treatment with H2 antagonists alone. The most effective treatment regimen currently available involves a 2-week course of triple therapy consisting of a bismuth compound together with metronidazole and either tetracycline or amoxycillin. However, there are problems associated with the triple therapy approach to eradicating H. pylori, such as non-compliance due to the taste and number of tablets and capsules needed, the onset of side effects such as nausea, diarrhea and dizziness, and the ineffectiveness against antibiotic-resistant strains of H. pylori. Other approaches include the use of sulfated glyceroglucolipids (U.S. Pat. No. 5,116,821). Collectively, these studies indicate that better ways of achieving consistent long-term eradication of H. pylori are needed.
The unsaturated fatty acids arachidonic acid and .omega.-3 linolenic acid have been reported to have an inhibitory effect on H. pylori (Hazell S. L., Graham D. Y., Unsaturated Fatty Acids and Viability of Helicobacter (Campylobacter) pylori J. Clin. Microbial. 1990; 1060-61; Thompson L., Cockayne A., Spiller R. C. Inhibitory Effect of W-3 linolenic Acid on the Growth of Helicobacter pylori, Abstract PL4 V Workshop on Gastroduodenal Pathology and Helicopter pylori, Jul. 5-7, 1992, In Irish Journal of Medical Science). Heretofore, the use of monoglycerides of C.sub.4 -C.sub.17 fatty acids to inhibit Helicobacter pylori has been unknown.